INTRODUCTION — Wilson disease (hepatolenticular degeneration) is a genetic disorder of copper metabolism with an autosomal recessive pattern of inheritance due to mutations that lead to impaired function of the intracellular copper transporter ATP7B. It is found worldwide, with a prevalence of approximately one case in 30,000 live births in most populations. Impaired biliary copper excretion leads to accumulation of copper in several organs, most notably the liver, brain, and cornea. Over time, the liver is progressively damaged and eventually becomes cirrhotic. The rate at which this occurs varies between patients. A small percent of patients (approximately 5 percent) develop acute injury (without encephalopathy) that progresses to acute liver failure, most often in the setting of advanced fibrosis of the liver. In addition, patients may develop neurologic and psychiatric complications, which can be severe.
This topic will review the clinical manifestations, diagnosis, and natural history of Wilson disease. The epidemiology, pathogenesis, and treatment of Wilson disease, as well as a detailed discussion of the individual tests used to diagnose Wilson disease, are discussed separately. (See "Wilson disease: Epidemiology and pathogenesis" and "Wilson disease: Diagnostic tests" and "Wilson disease: Treatment and prognosis".)
CLINICAL MANIFESTATIONS — The clinical manifestations of Wilson disease are predominantly hepatic, neurologic, and psychiatric, with many patients having a combination of symptoms . A non-immune hemolysis is also a common finding in patients with acute liver failure due to Wilson disease, but may occur episodically independent of liver failure.
Patients may present with a wide variety of symptoms (especially those with neurologic symptoms) [2,3]. Even within a given family, patients often present with different symptoms . There is wide variability in the reported rates of the different clinical manifestations seen at the time of presentation [2,5-15]:
●Liver disease: 18 to 84 percent of patients
●Neurologic symptoms: 18 to 73 percent of patients
●Psychiatric symptoms: 10 to 100 percent of patients
The wide variability in the estimates may in part be attributable to lead-time bias with respect to the age at which a patient is seen, as well as ascertainment bias based upon the clinical specialty to which the patient was referred (eg, to pediatricians where neurologic presentations are less likely, or to neurologists who are likely to see patients with neurologic symptoms).
Regardless of whether clinical manifestations are initially present, patients often develop other clinical manifestations as the disease progresses (eg, patients who present with liver disease may subsequently develop neurologic or psychiatric symptoms). Conversely, liver failure may develop in those whose neurologic or psychiatric symptoms led to the diagnosis of Wilson disease.
Age at symptom onset — The mechanisms for copper excretion are not well developed in newborns and begin to function more efficiently within the first year of life. For patients with Wilson disease, a critical ATP7B-dependent copper excretory pathway fails to develop or is dysfunctional, and copper accumulation that begins at birth continues throughout life, gradually producing clinical disease . The majority of patients with Wilson disease are diagnosed between the ages of 5 and 35 years (mean age of 13 years) , though this disorder has been diagnosed in younger patients and in patients in their eighth decade [1,13,17,18]. In a study of 143 children with Wilson disease, 21 children (15 percent) presented with symptoms or abnormal liver function tests before the age of five years . (See "Wilson disease: Epidemiology and pathogenesis".)
Children most often initially present with liver disease at an average age of 9 to 13 years [19,20], with Wilson disease accounting for 8 to 10 percent of chronic active hepatitis in children . Children diagnosed through family screening because of an affected sibling are often asymptomatic. In most patients, liver disease progresses silently, often until adolescence and beyond, when complications of cirrhosis or acute liver failure may develop. In some patients, neurologic or psychiatric manifestations precede overt liver disease.
While children are more likely to present with hepatic manifestations and rarely with neurologic symptoms, adolescents and adult patients present more often with neurologic manifestations. The mean age at presentation for patients with neurologic symptoms ranges between 15 and 21 years [2,19,22,23].
The variability in the age of onset of Wilson disease probably reflects differences in mutations and penetrance, extragenic factors, and environmental influences including diet . (See "Wilson disease: Epidemiology and pathogenesis", section on 'Pathogenesis'.)
Hepatic disease — The liver is the initial site of copper accumulation in patients with Wilson disease, and there are several different clinical manifestations due to hepatic copper accumulation [25,26]. Hepatic manifestations range from asymptomatic biochemical abnormalities often with steatosis to acute hepatitis and acute liver failure (with an associated Coombs-negative hemolytic anemia), chronic hepatitis, and cirrhosis. Regardless of presenting symptoms, some degree of liver disease, even if only histologic change, is usually present at the time Wilson disease is diagnosed .
The signs, symptoms, laboratory findings, and imaging findings in patients with hepatic Wilson disease vary with the degree of liver damage [1,2,28].
Signs and symptoms of hepatic Wilson disease may include:
●Kayser-Fleischer rings, visible in approximately 50 percent of patients at the time of presentation with hepatic disease (seen with all forms of liver involvement)
●Asymptomatic (steatosis, chronic hepatitis, compensated cirrhosis)
●Abdominal pain (acute hepatitis, acute liver failure)
●Jaundice (acute hepatitis, acute liver failure with hemolytic anemia, cirrhosis)
●Hepatomegaly (acute and chronic hepatitis, acute liver failure)
●Splenomegaly (cirrhosis with portal hypertension)
●Ascites (cirrhosis with portal hypertension)
●Upper gastrointestinal bleeding (cirrhosis with varices or portal hypertensive gastropathy)
●Peripheral stigmata of chronic liver disease (cirrhosis)
●Mental status changes due to hepatic encephalopathy (acute liver failure, cirrhosis with hepatic insufficiency and portosystemic shunting)
Laboratory test findings may include:
●Low level of serum ceruloplasmin (seen with all forms of liver involvement, though not as consistently with acute liver failure)
●Elevated aminotransferases (all forms of liver involvement)
●Thrombocytopenia (cirrhosis with splenomegaly)
●Coagulopathy (cirrhosis with hepatic insufficiency or acute liver failure)
●Coombs-negative hemolytic anemia (often seen in conjunction with acute liver failure, but can occur as episodic hemolysis without liver failure)
Abdominal imaging may show:
●Hepatic steatosis (chronic hepatitis)
●Hepatomegaly (hepatic inflammation)
●A small, nodular liver (cirrhosis)
The frequencies of various findings have been reported in several series [1,13,19,20,29-32]:
●Low ceruloplasmin: 95 percent with asymptomatic or chronic presentation
●Kayser-Fleischer rings: 50 percent with hepatic disease; 98 percent with neurologic or psychiatric presentation
●Acute liver failure: 5 percent
●Hepatomegaly and/or splenomegaly: 15 to 49 percent
●Jaundice, anorexia, and vomiting: 14 to 44 percent
●Fatty liver: 13 percent
●Ascites and/or edema: 5 to 50 percent
●No symptoms: 5 to 23 percent
●Variceal hemorrhage: 3 to 10 percent
●Hemorrhagic diathesis: 3 to 8 percent
●Hemolysis: 1 to 20 percent
Acute hepatitis and acute liver failure — Patients with Wilson disease, most often children or young adults, may develop acute hepatitis that is indistinguishable from acute viral hepatitis, with elevated aminotransferase levels, jaundice, and abdominal pain . The degree of aminotransferase elevation in patients with Wilson disease is usually less compared with patients with acute viral hepatitis or ischemic hepatitis. In some patients, the symptoms will resolve spontaneously (though Wilson disease is still present and requires treatment), whereas others may rapidly deteriorate and develop acute liver failure. Acute liver failure refers to the rapid (typically in less than 8 to 12 weeks) development of severe acute liver injury with impaired synthetic function with coagulopathy and encephalopathy in a person who previously had a normal liver. In Wilson disease, the development of acute liver failure differs in that it is development of acute-on-chronic liver disease, as most patients have advanced fibrosis or cirrhosis at the time of development of acute liver failure . (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis", section on 'Introduction'.)
Wilson disease accounts for approximately 5 percent of patients with acute liver failure who are referred for emergency transplantation. The female to male ratio of patients with acute liver failure due to Wilson disease is 2:1 to 4:1 [1,34].
Features seen in patients with acute liver failure due to Wilson disease include:
●A Coombs-negative hemolytic anemia. This is usually present in patients with acute liver failure due to Wilson disease and results from the effects of excess copper ions on the red blood cell membrane in the circulation due to hepatic copper release following cellular necrosis [26,35-38]. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)
●Serum aminotransferases that are typically less than 2000 international unit/L. The ratio of the AST to ALT is often >2.
●The alkaline phosphatase may be normal or markedly subnormal (<40 international unit/L), and the ratio of the alkaline phosphatase (international unit/L) to total bilirubin (mg/dL) is typically <4.
●Low uric acid levels.
●A coagulopathy that is unresponsive to vitamin K.
●Rapidly progressive renal failure.
Levels of ceruloplasmin are less reliable for diagnosing acute liver failure due to Wilson disease because ceruloplasmin is an acute phase reactant which may elevate levels  or levels can be depressed due to severe hepatic synthetic dysfunction.
Chronic hepatitis and cirrhosis — Patients with chronic hepatitis due to Wilson disease are often asymptomatic from their liver disease. Such patients are typically diagnosed through family screening, after being found to have abnormal liver tests, or after presenting with neurologic or psychiatric manifestations of Wilson disease. In addition, Wilson disease often results in hepatic steatosis and may be diagnosed in a patient being evaluated for nonalcoholic fatty liver disease .
Most of these patients have a low level of serum ceruloplasmin, but only 50 percent have Kayser-Fleischer rings. Almost all have liver copper concentrations of >250 mcg/g dry weight liver, but some have levels as low as 75 mcg, with normal being less than 40 mcg .
As the disease progresses, patients develop hepatic fibrosis and may present with evidence of compensated or decompensated cirrhosis, such as jaundice, ascites, thrombocytopenia, splenomegaly, palmar erythema, and variceal hemorrhage. In addition, patients may come to attention when abdominal imaging obtained for other reasons reveals evidence of cirrhosis or is suggestive of portal hypertension. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)
Cirrhosis is present at the time of diagnosis of Wilson disease in approximately 35 to 45 percent of patients overall [39-41], including those presenting with neuropsychiatric symptoms or who are asymptomatic [23,34,39,42]:
●In a series that included 14 patients over the age of 40 years who presented with neurologic symptoms and underwent liver biopsy, significant fibrosis was present in 10 (71 percent; 9 with cirrhosis and 1 with advanced fibrosis) .
●In a series with 34 patients with neurologic Wilson disease, 14 (41 percent) were found to have cirrhosis .
●In a study that included 18 asymptomatic patients detected through screening because of an affected sibling, two (11 percent) had cirrhosis at the time of diagnosis .
Neurologic manifestations — The reported neurologic manifestations of Wilson disease are broad and diagnosing neurologic Wilson disease can be challenging because patients present in a myriad of ways. Nearly all (98 percent) of patients with Wilson disease with neurologic manifestations have Kayser-Fleischer rings. Neurologic symptoms may be very subtle or may be rapidly progressive, leading to severe disability over the course of months . In patients with known cirrhosis, neurologic manifestations may be mistaken for hepatic encephalopathy.
The majority of patients with neurologic Wilson disease fall into one of several categories: dysarthric, dystonic, tremulous, pseudosclerotic (tremor with or without dysarthria), or parkinsonian . Initially, only one symptom may be present, but as the disease progresses, complex combinations of neurologic signs and symptoms may develop.
Some of the more common neurologic manifestations include:
●Dysarthria – 85 to 97 percent of patients with neurologic Wilson disease
●Gait abnormalities/ataxia – 30 to 75 percent
●Dystonia – 11 to 69 percent
●Tremor – 22 to 55 percent
●Parkinsonism – 19 to 62 percent
●Drooling – 48 to 86 percent
Other neurologic manifestations include:
●Risus sardonicus (sardonic expression produced by dystonic spasm of the facial muscles)
Magnetic resonance imaging (MRI) or computed tomographic (CT) scanning of the brain may reveal structural abnormalities in the basal ganglia in patients with neurologic Wilson disease . Common findings in the regions of the basal ganglia include increased density on CT scan and hyperintensity on T2-weighted MRI images. Other findings include hyperintensities in the tectal-plate and central pons. Simultaneous involvement of the basal ganglia, thalamus, and brainstem is highly suggestive of Wilson disease .
Cerebrospinal fluid (CSF) copper concentrations in patients with neurologic Wilson disease are elevated three to fourfold relative to those in patients without Wilson disease or with Wilson disease without neurologic signs . These values fall with treatment  but are not typically followed for clinical purposes as the gradual disappearance of Kayser-Fleischer rings indicates dissipation of copper in the central nervous system.
Dysarthria — Among patients with neurologic Wilson disease, dysarthria is the most common neurologic symptom. The type of dysarthria may vary: patients may have ataxic dysarthria (irregular word spacing and volume), or the speech may be athetoid, hypophonic, or spastic .
Dystonia — Dystonia associated with Wilson disease may range in severity from mild to debilitating and often worsens with disease progression . It may be focal, segmental, multifocal, or generalized. While it can occur unilaterally, it may eventually become bilateral or generalized. In some patients with severe dystonia, contractures may develop and may only be corrected surgically by tendon lengthening. (See "Etiology, clinical features, and diagnostic evaluation of dystonia".)
Focal manifestations of dystonia include blepharospasm, cervical dystonia (torticollis), writer's cramp, and a dystonic facial expression in which the patient appears to have an exaggerated smile (risus sardonicus). With focal dystonia of the vocal cords, muscles of articulation, or swallowing muscles, patients may develop dysphonia, dysarthria, or dysphagia, respectively.
Tremor — Tremors in Wilson disease may occur at rest or with action and may have multiple position and task-dependent characteristics . Some of the tremors seen include:
●A tremor that resembles essential tremor (variable amplitude and frequency, with arm and sometimes head and leg involvement). Unlike essential tremor, the tremor in patients with Wilson disease often persists in its asymmetry and may not involve the voice. (See "Overview of tremor", section on 'Essential tremor'.)
●An intention (kinetic) tremor (low amplitude, medium-to-high frequency), seen most often in a distal upper extremity. Intention tremors typically increase in severity as the patient's hand moves closer to its target. (See "Overview of tremor", section on 'Cerebellar tremor'.)
●A postural tremor that occurs when the patient assumes a particular position. The classic tremor associated with Wilson disease is a wing-beating tremor, though it is not the most common type of tremor . The tremor is a low-frequency, high-amplitude tremor that is most prominent when the patient's arms are held outstretched laterally or with the arms extended in front of the patient with the palms facing downward and the elbows flexed. The tremor increases in amplitude with increased duration of posture holding. The name comes from the fact that the movement of the patient's arms may be reminiscent of a bird's flapping wings.
●A unilateral rest tremor may be present, but is rarely seen in isolation. When present, it is typically accompanied by postural and intention tremors that often dominate the clinical picture .
Parkinsonism — Parkinsonian features that may be seen in Wilson disease include bradykinesia, cogwheel rigidity, and postural instability. Parkinsonism is rarely an isolated clinical feature in patients with Wilson disease and is typically accompanied by other neurologic deficits. .
Choreoathetosis — Chorea is characterized by rapid and unpredictable contractions affecting mostly distal limbs, but it can also affect the face and trunk. The movements are involuntary and non-patterned with variable speed, timing, and direction, flowing from one body part to another. In less severe cases, this can result in an appearance of fidgetiness. The unpredictable nature of chorea is a feature that distinguishes it from tremor and dystonia . When severe and with proximal muscle involvement, choreic movements may result in violent, uncontrolled flailing movements of the extremities (ballism). Athetosis refers to slower writhing movements with a sinuous quality. The term choreoathetosis is used when typical choreic movements coexist with athetosis. (See "Overview of chorea".)
Chorea as an initial clinical feature is more often seen in younger patients (≤16 years). It has been reported in 20 percent of patients with a young age of symptom onset, compared with 3 percent of patients with an older age of onset . It typically is not present in isolation .
Cerebellar ataxia — Cerebellar ataxia is generally not seen as the sole neurologic manifestation of Wilson disease . The ataxia is typically not clinically relevant, and frank limb ataxia is uncommon.
●Overshoot in point-to-point movements (dysmetria)
●In multijoint movements, breakdown of normal coordination of joint rotations, with trajectory abnormalities (dyssynergia)
●Breakdown in the rhythm of repetitive, alternating single movements, such as finger tapping (dysrhythmia)
Dysfunction in the vermis or paleocerebellum results in truncal and gait ataxia. (See "Causes and evaluation of neurologic gait disorders in older adults", section on 'Cerebellar ataxia'.)
Cognitive impairment — Two main categories of cognitive impairment in Wilson disease have been described, a frontal syndrome and subcortical dementia, with some patients having features of both . In patients with cognitive impairment, the findings can be subtle and may only be recognized retrospectively. In addition, some have suggested that the apparent cognitive impairment may be primarily the result of psychiatric and motor manifestations of Wilson disease [14,50]. In those with new changes in cognition, it is important to exclude hepatic encephalopathy that may be reversible.
Patients with a frontal syndrome may demonstrate impulsivity, promiscuity, impaired judgement, apathy, executive dysfunction (poor planning and decision making), decreased attention, and emotional lability. When severe, patients may have pseudobulbar features (sudden outbursts of inappropriate laughter or tearfulness). (See "Frontotemporal dementia: Clinical features and diagnosis", section on 'Behavioral variant FTD'.)
Findings in subcortical dementia include slowed thinking, memory loss, and executive dysfunction. It lacks cortical signs such as aphasia, apraxia, or agnosia.
Other neurologic features — Seizures, while rarely the presenting feature, are seen in approximately 6 percent of patients with Wilson disease and have been associated with the initiation of chelation therapy but may occur later on . Other neurologic manifestations include hyperreflexia, tics, and unusual stereotyped movements . Dysautonomia, such as abnormal cardiac responses to the Valsalva maneuver, may occur in patients with Wilson disease, but when present is usually found in those with other neurologic signs and symptoms due to Wilson disease . It is thought to be due to central nervous system involvement.
Behavioral and psychiatric symptoms — Behavioral and psychiatric symptoms are more common in patients with neurologic involvement than in patients with hepatic involvement [50,53]. However, psychiatric symptoms may precede the recognition of hepatic or neurologic Wilson disease by a significant period of time. The most common behavioral and psychiatric symptoms include depression (reported in 20 to 30 percent of patients with Wilson disease), personality change, incongruous behavior, and irritability [2,50]. However, behavioral and psychiatric symptoms due to Wilson disease are often misdiagnosed (eg, they may be attributed to puberty). As a result, it is uncommon for patients to be diagnosed with Wilson disease when the only manifestations are behavioral or psychiatric, and diagnosis may be delayed significantly in these individuals.
Behavioral and psychiatric manifestations of Wilson disease include [1,2,25,50,54-56]:
●Declining school performance
●Personality changes (which may be subtle)
●Bipolar affective disorder
Hemolysis — Infrequently, Coombs-negative hemolytic anemia may be the initial symptom of Wilson disease and is not uniformly associated with acute liver failure [19,57]. In a series of 283 patients, hemolytic anemia was the sole presenting feature in only three patients (1 percent), but it was present in a 19 of 77 patients (28 percent) who had jaundice at presentation . The hemolytic anemia may occur as a single acute episode, or it may be low-grade, episodic, or chronic.
Patients reporting a history of jaundice prior to the diagnosis of Wilson disease may have had previously unrecognized hemolysis . If acute hepatitis and hemolysis due to Wilson disease develop during pregnancy, it may be mistaken for HELLP syndrome. In those with acute liver failure due to Wilson disease, a hemoglobin <10 g/dL is associated with a 94 percent sensitivity but only 74 percent specificity for this diagnosis . (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)
Ocular manifestations — Kayser-Fleischer rings are brownish rings that are due to fine, pigmented, granular deposits of copper in Descemet's membrane in the cornea (picture 1). Kayser-Fleisher rings are thought to reflect copper within the central nervous system, and they dissipate over time with treatment directed towards the removal of copper. Kayser-Fleischer rings are a characteristic feature of Wilson disease and are seen in approximately 98 percent of patients with neurologic manifestations, but only 50 percent of patients with hepatic manifestations. While often only detected by slit-lamp examination (typically done in a patient already suspected of having Wilson disease), Kayser-Fleischer rings are sometimes visible without a slit-lamp examination when they are sizable, especially in those with lighter colored irises where the contrast between the background color makes it more obvious. Optical tomography has been applied to visualize Kayser-Fleischer rings and has the advantage of providing an objective observation that also permits quantitation of the ring size . However, Kayser-Fleisher rings are rarely the first finding in a patient with Wilson disease. (See "Wilson disease: Diagnostic tests" and "Slit lamp examination".)
Sunflower cataracts are another ocular manifestation of Wilson disease and occur when copper deposits accumulate in the lens. These, too, are generally seen with a slit-lamp examination.
Other manifestations — Wilson disease can cause abnormalities related to copper deposition in other organs. Other manifestations of Wilson disease that are less common include [1,60-62]:
●Fanconi syndrome, in which proximal tubular dysfunction leads to glucosuria, aminoaciduria, hypouricemia, and proximal renal tubular acidosis. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'.)
●Nephrolithiasis secondary to distal renal tubular acidosis. (See "Nephrolithiasis in renal tubular acidosis".)
●Arthropathy with features of premature arthritis and occasionally chondrocalcinosis, most commonly in the knee.
●Infertility or repeated spontaneous abortions.
●A variety of dermatologic disorders. These include blue lunulae (lunulae ceruleae), acanthosis nigricans, and pretibial hyperpigmentation. Dermatologic manifestations may also occur from treatment with penicillamine, including progeric change to the skin (commonly seen around the neck), bullous pemphigoid, elastosis perforans serpiginosa, and pseudoxanthoma elasticum [63-65].
Abnormal liver tests or cirrhosis — Abnormal aminotransferases may be seen in many liver disorders, including viral hepatitis, alcohol use disorder, autoimmune hepatitis, hepatotoxicity due to drugs or supplements, hereditary hemochromatosis, and alpha-1 antitrypsin deficiency. In patients with Wilson disease, the serum aminotransferases are usually mildly to moderately elevated, and the aspartate aminotransferase (AST) concentration is usually higher than the alanine aminotransferase (ALT) concentration. (See "Approach to the patient with abnormal liver biochemical and function tests".)
Similarly, in patients presenting with cirrhosis, other causes of chronic liver disease, such as viral hepatitis, need to be considered. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis".)
Acute liver failure — Acute liver failure has many causes, including toxin ingestion, viral hepatitis, ischemia, inherited metabolic diseases, and autoimmune hepatitis. Among patients with acute liver failure due to Wilson disease, the serum aminotransferases are typically less than 2000 units/L with an AST/ALT ratio of >2 [33,34]. In addition, the alkaline phosphatase level is typically normal or subnormal, with an alkaline phosphatase (international unit/L) to total bilirubin (mg/dL) ratio of <4. Finally, patients with acute liver failure due to Wilson disease typically develop a Coombs-negative hemolytic anemia and may have a low uric acid level. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis" and "Acute liver failure in children: Etiology and evaluation".)
Neurologic manifestations — The neurologic manifestations of Wilson disease are numerous and can mimic other neurologic disorders, especially any type of movement disorder. Disorders that should be considered include essential tremor, young-onset Parkinson disease, and generalized dystonia. Disorders that may rarely mimic Wilson disease include Huntington disease, pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz disease), idiopathic torsion dystonia, chorea-acanthocytosis, and benign familial chorea. The presence of Kayser-Fleischer rings, seen in approximately 98 percent of patients with neurologic Wilson disease, can help differentiate Wilson disease from other disorders. In addition, patterns of injury on magnetic resonance imaging (MRI) or computed tomography (CT) of the brain may suggest the diagnosis of Wilson disease . (See "Overview of tremor" and "Etiology, clinical features, and diagnostic evaluation of dystonia" and "Bradykinetic movement disorders in children" and "Neuroacanthocytosis", section on 'Chorea-acanthocytosis' and "Neuroacanthocytosis", section on 'Mcleod syndrome' and "Neuroacanthocytosis", section on 'Huntington disease-like 2'.)
Psychiatric manifestations — The differential diagnosis for the psychiatric manifestations of Wilson disease includes disorders such as depression, bipolar disorder, schizophrenia, dementia, and drug abuse. As with the neurologic manifestations, the presence of Kayser-Fleischer rings can often help differentiate patients with Wilson disease from these other disorders. (See "Unipolar depression in adults: Assessment and diagnosis" and "Bipolar disorder in adults: Epidemiology and pathogenesis" and "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis".)
DIAGNOSIS — The diagnosis of Wilson disease starts with recognition of the clinical features suggestive of the disease or identification of family members who require screening. Testing begins with serologic testing (liver biochemical tests, a complete blood count, and serum ceruloplasmin level), an ocular slit-lamp examination (or optical tomography), and 24-hour urinary copper excretion (algorithm 1). Only approximately one-half of patients ultimately diagnosed with Wilson disease present with the classic clinical picture of a patient between the ages of 5 and 35 years with a decreased serum ceruloplasmin and detectable Kayser-Fleischer rings . Family screening of siblings should now begin with mutation analysis for ATP7B mutations if the identified patient (proband) has been tested and both mutations are identified. (See 'Clinical manifestations' above.)
When to consider Wilson disease — Wilson disease should be considered in any patient with unexplained liver, neurologic, or psychiatric abnormalities or in a first-degree relative of a patient with Wilson disease. A scoring system for helping to determine the need to continue with diagnostic testing for Wilson disease and determine the certainty of diagnosis was developed at an international meeting in Leipzig . This scoring system included clinical and laboratory testing, and results yielded three categories of patients: those in whom other diagnoses should be considered, those in whom further diagnostic testing is needed, and those in whom there is certainty as to diagnosis.
Patients are allotted points if any of the following are present (if information is missing for a given item, the patient is assigned 0 points for that item):
●Kayser-Fleischer rings (2 points)
●Neuropsychiatric symptoms suggestive of Wilson disease (2 points)
●Coombs-negative hemolytic anemia with high serum copper (1 point)
●Urinary copper in the absence of acute hepatitis
•One to two times the upper limit of normal (1 point)
•>2 times the upper limit of normal (2 points)
•Normal, but >5 times the upper limit of normal after challenge with two doses of 0.5 g D-penicillamine (2 points)
●Liver copper quantitative measurement
•Normal (-1 point)
•Up to five times the upper limit of normal (1 point)
•>5 times the upper limit of normal (2 points)
●Rhodanine positive hepatocytes (if unable to obtain quantitative copper measurement) (1 point)
●Serum ceruloplasmin (based on using a nephelometric assay with a normal value >20 mg/dL)
•Normal (0 points)
•10 to 20 mg/dL (1 point)
•<10 mg/dL (2 points)
•Disease causing mutations on both chromosomes (4 points)
•Disease causing mutations on one chromosome (1 point)
•No disease causing mutation (0 points)
If the score is ≥4, Wilson disease is highly likely; if it is 3, the diagnosis is probable, but more investigation is warranted (eg, obtaining a liver biopsy if not already done); if it is ≤2, Wilson disease is unlikely.
Serum aminotransferases are usually mildly to moderately elevated in patients with Wilson disease diagnosed in a presymptomatic stage. The degree of elevation correlates poorly with the extent of histologic injury [30,67]. The aspartate aminotransferase (AST) concentration is usually higher than the alanine aminotransferase concentration (ALT). (See 'Hepatic disease' above.)
Neurologic disorders in patients with Wilson disease include a parkinsonian-like rest tremor, rigidity, clumsiness of gait, slurring of speech, facial grimacing (risus sardonicus), and drooling. Patients may also present with psychiatric problems, ranging from subtle personality changes and deteriorating performance at school, to overt depression or psychosis. (See 'Neurologic manifestations' above and 'Behavioral and psychiatric symptoms' above.)
While the majority of patients diagnosed with Wilson disease are between the ages of 5 and 35 years, Wilson disease has been diagnosed in patients as young as 18 months of age and in patients who are in their 70s. (See 'Age at symptom onset' above.)
●Patients with liver abnormalities of uncertain etiology, especially in those with liver disease accompanied by neurologic or psychiatric symptoms or with a family history of Wilson disease.
●Pediatric patients, and less commonly adults, with clinical features suggestive of autoimmune hepatitis, especially if there is no response or inadequate response to standard treatments for autoimmune hepatitis with glucocorticoids, as there have been rare instances of concurrent disease. (See "Overview of autoimmune hepatitis".)
●Patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis (steatosis is a common finding in Wilson disease) with atypical features for nonalcoholic fatty liver disease (such as absence of obesity) or who are under the age of 35 years. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)
●Patients with acute liver failure with features suggestive of Wilson disease. (See 'Acute hepatitis and acute liver failure' above.)
●First-degree relatives of a patient diagnosed with Wilson disease.
Initial evaluation — The initial evaluation of a patient suspected of having Wilson disease starts with noninvasive testing (serologic tests, ocular examination, and determination of urinary copper excretion) (algorithm 1). Additional testing, such as a liver biopsy, may be required if the initial testing is inconclusive.
We start the evaluation with:
●Determination of liver biochemical tests to look for evidence of active inflammation and to assess the AST to ALT ratio (often >2 in patients with Wilson disease).
●A complete blood count to look for anemia (followed by testing for Coombs-negative hemolytic anemia if indicated) (see "Diagnosis of hemolytic anemia in adults") and to look for the presence of thrombocytopenia, which might indicate hypersplenism due to portal hypertension.
●Measurement of the serum ceruloplasmin concentration. (See "Wilson disease: Diagnostic tests", section on 'Serum ceruloplasmin concentration'.)
●Measurement of the serum copper concentration. (See "Wilson disease: Diagnostic tests", section on 'Serum copper concentration'.)
●An ocular slit-lamp examination. (See "Wilson disease: Diagnostic tests", section on 'Ocular slit-lamp examination'.)
●Determination of 24-hour urinary copper excretion. (See "Wilson disease: Diagnostic tests", section on 'Urinary copper excretion'.)
●Tests to rule out other causes of hepatic, neurologic, or psychiatric symptoms that could mimic Wilson disease. (See 'Differential diagnosis' above.)
●Molecular testing for ATP7B mutations in siblings of affected patients (if such testing is available for the proband).
Interpretation of test results — Our interpretation of the initial laboratory test results and our approach to additional testing is as follows. This approach is similar to that outlined in a consensus guideline from the American Association for the Study of Liver Diseases (table 1 and algorithm 2 and algorithm 1) [34,68] and a guideline from the European Association for the Study of the Liver .
Low ceruloplasmin (<20 mg/dL or 200 mg/L), low serum copper concentration
●Kayser-Fleischer rings present:
•A diagnosis of Wilson disease is established if the 24-hour urinary copper excretion is >40 mcg (0.64 micromol).
•If urinary copper excretion is ≤40 mcg (0.64 micromol), a liver biopsy should be obtained to stain for copper and to determine the hepatic copper concentration, or molecular genetic testing for ATP7B mutations may be performed. (See "Wilson disease: Diagnostic tests", section on 'Liver biopsy'.)
●Kayser-Fleischer rings absent:
•A diagnosis of Wilson disease is established if the 24-hour urinary copper excretion is >100 mcg (1.6 micromol). However, in the setting of acute liver injury, urinary copper may be elevated to this level, and further testing such as liver biopsy or molecular testing is suggested.
•If the urinary copper excretion is ≤100 mcg (1.6 micromol), a liver biopsy should be obtained to determine the hepatic copper concentration, or molecular genetic testing for ATP7B mutations may be performed.
Normal or elevated ceruloplasmin (≥20 mg/dL or 200 mg/L), normal serum copper concentration
●Kayser-Fleischer rings present:
•A liver biopsy should be obtained to stain for copper and to determine the hepatic copper concentration, regardless of urinary copper excretion, or molecular genetic testing for ATP7B mutations may be performed. (See "Wilson disease: Diagnostic tests", section on 'Liver biopsy'.)
●Kayser-Fleischer rings absent:
•A diagnosis of Wilson disease is excluded if the urinary copper excretion is ≤40 mcg (0.64 micromol).
•If the urinary copper excretion is >40 mcg (0.64 micromol), a liver biopsy should be obtained to stain for copper and to determine the hepatic copper concentration, or molecular genetic testing for ATP7B mutations may be performed.
Hepatic copper concentration — Patients who undergo a liver biopsy should have their hepatic copper concentration determined (see "Wilson disease: Diagnostic tests", section on 'Hepatic copper concentration'):
●A diagnosis of Wilson disease is established if the hepatic copper concentration is ≥250 mcg/g dry weight (4 micromol/g dry weight).
●A diagnosis of Wilson disease is excluded if the hepatic copper concentration is <50 mcg/g dry weight (0.8 micromol/g dry weight). Rarely, sampling variation (eg, sampling only scar tissue in a patient with cirrhosis) may lead to a falsely normal hepatic copper concentration in a patient with Wilson disease [26,39,69,70]. If the urinary copper excretion is >100 mcg (1.6 micromol), the patient most likely has Wilson disease.
If the hepatic copper concentration is between 50 and 250 mcg/g dry weight, especially if histology reveals evidence of active liver disease, molecular genetic testing for ATP7B mutations is indicated to establish the diagnosis. Molecular genetic testing is also indicated if there is suspicion of sampling variation leading to a falsely normal hepatic copper concentration. (See "Wilson disease: Diagnostic tests", section on 'Genetic testing'.)
Scoring system for establishing a diagnosis of Wilson disease — Criteria were developed at a consensus meeting held at an international meeting on Wilson and Menkes disease in Leipzig, Germany . This scoring system was the first to give weighted numeric values for the testing described above. These include specific biochemical testing (including ceruloplasmin, urine copper, and hepatic copper), clinical manifestations of Wilson disease (presence of Kayser-Fleischer rings and neurologic manifestations), and molecular testing for ATP7B mutations. A score of only 1 or 2 after all the testing is done excludes Wilson disease, while a score of 3 suggests further evaluation is needed and a score of 4 or more is diagnostic for Wilson disease. This scoring system has been validated in adults and children and also has been incorporated into European Association for the Study of the Liver guidelines for the diagnosis and treatment of Wilson disease (table 2) .
Screening family members — First-degree relatives of patients diagnosed with Wilson disease should be screened for the disease (algorithm 2). Among siblings, molecular genetic testing based upon the proband should be performed if possible. Genotyping for polymorphisms around the Wilson disease gene may also be performed; however, direct mutation analysis has become more available, and targeted testing of siblings makes this very specific and more economical. (See "Wilson disease: Diagnostic tests", section on 'Genetic testing'.)
For the child of a patient with Wilson disease and in those individuals where molecular genetic testing is not possible, the evaluation with clinical and biochemical testing is the same as that for a patient with clinical features suggestive of Wilson disease. (See 'Initial evaluation' above.)
Progression of disease — Untreated, Wilson disease is universally fatal . Copper accumulation in the liver eventually leads to the development of cirrhosis, and among patients with neurologic Wilson disease, the neurologic disease may progress until the patient becomes severely dystonic, akinetic, and mute. Progression is usually gradual, but sudden deterioration may also occur. The majority of patients will die from liver disease (cirrhosis or acute liver failure), while the remainder die due to complications that arise due to progressive neurologic disease.
Survival — Data are lacking regarding life expectancy among untreated patients with Wilson disease. One study found that the median survival following the development of neurologic symptoms was approximately five years . Patients who develop acute liver failure due to Wilson disease have an acute mortality rate of at least 95 percent in the absence of a liver transplantation, with death occurring in days to weeks [1,5].
The prognosis for patients who receive and are adherent to treatment for Wilson disease is excellent, even in some who already have advanced liver disease. In patients without advanced liver disease, life expectancy is normal, though treatment may lead to worsening of neurologic symptoms in a fraction of patients, most often during the initiation of therapy [13,42].
Among patients requiring liver transplantation, most commonly for acute liver failure or advanced liver disease unresponsive to therapy, one-year survival following transplantation had been reported to be 79 to 90 percent [34,71]. Results from the United Network for Organ Sharing's Scientific Registry for Transplant in the United States found survival rates at one and five years for adults transplanted between 1987 and 2008 (n = 400) were 88 and 86 percent, respectively. For children transplanted between 2002 and 2008 (n = 170), the one- and five-year survival rates were 90 and 89 percent, respectively . Survival was higher in adults and children undergoing transplantation for chronic liver disease compared with those undergoing transplantation for acute liver failure. (See "Wilson disease: Treatment and prognosis".)
Cancer risk — Patients with Wilson disease, especially those with cirrhosis, are probably at increased risk for hepatocellular carcinoma (HCC). Whether they are at higher risk for other malignancies is unclear. Occasional reports have described HCC and cholangiocarcinoma occurring in the setting of Wilson disease, and screening for HCC is recommended for patients with cirrhosis due to Wilson disease [72-74]. (See "Surveillance for hepatocellular carcinoma in adults", section on 'Patients with cirrhosis'.)
One of the largest series to address the association of Wilson disease with cancer included a total of 363 patients seen at three centers in England since 1955, eleven of whom had been diagnosed with cancer . The cancers included cholangiocarcinoma (three patients), poorly differentiated adenocarcinoma of undetermined primary site (five patients) and HCC (three patients). The incidence of cancer appeared to be related to the duration of disease. No cancers were seen in patients followed for less than 10 years, compared with an incidence of 4.2 percent in those followed for 10 to 19 years, 5.3 percent for those followed for 20 to 29 years, and 15 percent for those followed for 30 to 39 years.
Whether the risk of cancer was increased compared with the general population is difficult to determine from this report since it did not include a control group. The higher incidence of cancer in those followed for longer may have been at least in part related to their older age and longer duration of follow-up. On the other hand, the types of cancer seen (occurring in organs affected by copper deposition) support a possible association with Wilson disease.
The risk for developing HCC in patients with Wilson disease was also examined in two studies from Europe. In the first study, the prevalence of hepatobiliary malignancies in 1186 patients with Wilson disease was 1.2 percent, and the incidence was 0.28 per 1000 person-years . In the second study, 130 patients were followed for a mean of 15 years, and two patients with HCC were found: one at time of diagnosis and the other after 50 years of treatment . The estimated annual HCC risk was 0.09 percent for patients overall and was 0.14 percent for patients with cirrhosis. In both of these studies, the annual incidence of HCC did not reach thresholds for which screening and surveillance for HCC are recommended (cost-effectiveness models suggest that in patients with cirrhosis, surveillance becomes cost-effective once the annual incidence of HCC exceeds 1.5 to 2 percent). However, given the ability to change survival with detection of early lesions, it may still be useful to do screening and surveillance by ultrasound, but the cost-effectiveness is not certain. (See "Surveillance for hepatocellular carcinoma in adults".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited liver disease".)
SUMMARY AND RECOMMENDATIONS
●Clinical features – The clinical manifestations of Wilson disease are predominantly hepatic, neurologic, and psychiatric, with many patients having a combination of symptoms. (See 'Clinical manifestations' above.)
•Age at symptom onset – The majority of patients with Wilson disease are diagnosed between the ages of 5 and 35, though it has been diagnosed in younger patients and in patients in their eighth decade of life. (See 'Age at symptom onset' above.)
•Hepatic manifestations – Hepatic manifestations include acute liver failure with a Coombs-negative hemolytic anemia, acute hepatitis, chronic hepatitis, cirrhosis, steatosis, and asymptomatic liver biochemical abnormalities. Regardless of presenting symptoms, some degree of liver disease is usually present at the time of diagnosis of Wilson disease. (See 'Hepatic disease' above.)
•Neurologic manifestations – The reported neurologic manifestations of Wilson disease are broad, and diagnosing neurologic Wilson disease can be challenging because patients present in many different ways. The majority of patients with neurologic Wilson disease have dysarthria and/or movement disorders. Initially, it is common for one symptom to be present (often unilaterally), but as the disease progresses, complex combinations of neurologic signs and symptoms may develop. (See 'Neurologic manifestations' above.)
•Behavioral and psychiatric symptoms – Behavioral and psychiatric symptoms are more common in patients with neurologic involvement than in patients with hepatic involvement. The most common behavioral and psychiatric symptoms include depression (reported in 20 to 30 percent of patients with Wilson disease), personality change, incongruous behavior, and irritability. (See 'Behavioral and psychiatric symptoms' above.)
•Other manifestations – Other clinical manifestations of Wilson disease include Coombs-negative hemolytic anemia and Kayser-Fleischer rings. (See 'Hemolysis' above and 'Ocular manifestations' above and 'Other manifestations' above.)
●Diagnosis – In patients with clinical features suggestive of Wilson disease, we start by obtaining liver biochemical tests, a complete blood count, serum ceruloplasmin and copper levels, an ocular slit-lamp examination, and a 24-hour urinary copper excretion (algorithm 1). The results of these tests determine the need for additional testing. (See 'Diagnosis' above.)
●Natural history – Untreated, Wilson disease is universally fatal. Copper accumulation in the liver eventually leads to the development of cirrhosis, and among patients with neurologic Wilson disease, the neurologic disease may progress until the patient becomes severely dystonic, akinetic, and mute. The majority of patients will die from liver disease (cirrhosis or acute liver failure), while the remainder die due to complications of progressive neurologic disease. (See 'Natural history' above.)
The prognosis for patients who receive and are adherent to treatment for Wilson disease is excellent, even in some who already have advanced liver disease. In patients without advanced liver disease, life expectancy is normal, though treatment may lead to worsening of neurologic symptoms in a fraction of patients. Among patients requiring liver transplantation, survival following transplantation is excellent. (See "Wilson disease: Treatment and prognosis".)
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